By recreating an extinct virus that killed as many as 50 million people, scientists race to defeat avian flu before it evolves into a deadlier form.

1) Surface proteins bind the virus particle, or virion, to the membrane of the doomed cell.

2) The virion passes into the cell, releasing strands of RNA with the virus's genetic material.

3) The RNA moves to the nucleus and hijacks the cell's biochemical machinery to copy itself.

4) New strands of RNA migrate to the outer cell, joining newly manufactured proteins to form complete viral particles.

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5) Emerging virion attack more cells, or are expelled in a sneeze to infect another host.

6) In the case of genetic reassortment, strands of RNA from two different virion may mix, creating a hybrid virus more deadly than either of its parents.

Last spring, microbiologist Terrence Tumpey was at work in his office at the Centers for Disease Control and Prevention (CDC) in Atlanta when a FedEx package arrived for him in the main reception area. Upon seeing the return address of his colleague Peter Palese, at the Mount Sinai School of Medicine in New York, Tumpey took the package to a high-containment lab and locked it in a freezer. The contents merited serious protection. Three vials of saline solution, each about the size of a ballpoint pen cap, held the genes of the virus responsible for the Spanish Flu of 1918--the deadliest influenza pandemic ever to hit mankind. By inserting the genes into human kidney cells, Tumpey soon would make a stunning biomedical breakthrough: bringing an extinct virus back to life.

A BOLD STRATEGY

By the end of World War I, the Spanish Flu had killed between 20 million and 50 million people worldwide. Then, 79 years later, another strain of avian flu jumped straight from birds to humans. Unlike the Spanish Flu, H5N1--first detected in Hong Kong in 1997--does not yet pass easily from human to human, a fact that has kept its death toll under 100. But that could change at any moment. A handful of the nation's top virologists are racing to develop new tools to fight H5N1 before the virus evolves, unleashing a pandemic. Their plan is to produce a deadly strain of influenza virus themselves, essentially beating nature to the punch. "The goal," says CDC spokesman Dave Daigle, "is to create the worst-case scenario so we can develop the best diagnostics, vaccines and antivirals offering the greatest protection."

PRIMITIVE BUT DEADLY

A flu virus is astonishingly simple. While a human being has some 25,000 genes, influenza has just eight. But nature has made the flu's genes supremely efficient. A virus particle, or virion, four-millionths of an inch across, can kill a host 10 million billion times its size.

Like a special forces team penetrating enemy headquarters, each gene has a specialty at which it is masterfully proficient. When a virion invades a cell, its flu genes hijack the host's biological machinery, using it to replicate a millionfold. New virion then burst out of the dying cell to repeat the cycle of infection. Eventually, the body begins producing antibodies that recognize and destroy the invader.

If every virion were the same, influenza would lose its menace. But one of the virus's most striking characteristics is its gift for rapid change. Influenza is wildly inaccurate in copying its genes, making up to a million times as many mistakes as human cells do. Most of these errors render the virus inoperable. But once in a while, mutations give the virus an edge. It's evolution in hyperdrive. Each accumulation of mutations is like a new spin on a slot machine; if the right combination comes up, the payoff for the virus can be staggering.

PICKING UP THE PIECES

Thanks to this genetic variability, several strains of flu circulate at any given time. While even mild strains can kill weak or elderly patients, one occasionally packs a truly lethal wallop. The Asian Flu of 1957-58 and the Hong Kong Flu of 1968-69 each killed between 1 million and 4 million people.

But no strain outmaneuvered the human immune system as efficiently as the Spanish Flu of 1918, and so no strain would offer a better model for understanding what makes a deadly flu virus tick. The problem? It became extinct decades ago.

In 1995, Jeffery K. Taubenberger, chair of the department of molecular pathology at the Armed Forces Institute of Pathology in Rockville, Md., began looking for traces of the virus in the institute's collection of 3 million forensic samples, which date back to 1862. After examining the remains of 78 soldiers who died during the 1918 pandemic, Taubenberger's team found fragments of virus in two of them. They also found fragments in the autopsy archives of the Royal London Hospital. But the pieces from both sources were short, no longer than 130 nucleotides--together, the virus's eight genes contain 13,600 nucleotides.

Two years later, when the media reported that Taubenberger had pieced together enough of the genes to confirm it was the 1918 flu, 72-year-old retired physician Johan Hultin read the news with interest. Back in 1951, when Hultin was a doctoral candidate in microbiology at the University of Iowa, he had recovered fragments of the 1918 virus from bodies buried in the Alaska permafrost. Although his attempts to infect ferrets with it had failed, he realized that advances in technology meant that now even minuscule fragments of decomposed genetic material could be used to decipher the virus's secrets. He contacted Taubenberger and volunteered to head north.

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Hultin returned to the mass grave in Brevig Mission, Alaska, that he had explored a half-century earlier. There he exhumed the corpse of a female flu victim and cut out 1-in. cubes of lung tissue. Dispatched to Taubenberger, the samples provided enough genetic material to finish sequencing all eight genes.

By comparing the complete sequence with known strains of human and avian flu, scientists were finally able to piece together what had happened. Somehow, a strain of influenza that normally lives harmlessly in the gut of a bird had accumulated just the right mutations to make it deadly to humans--and worse, transmissible from human to human. But which changes were the crucial ones?

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RESURRECTION

One way to find out would be to use the genetic sequence--the blueprints of the virus--to build the 1918 flu and see how it works. And so, as Taubenberger's team sequenced the flu's genes one by one, Palese's team at Mount Sinai synthesized the sequences and stitched them into loops of bacterial DNA. These were the genes Palese sent by FedEx to Atlanta, and Tumpey inserted into human kidney cells for replication. The more components of the 1918 flu he received, the more potent the virus that Tumpey was able to create. With the shipment of the remaining three genes last spring, he was finally able to inject the entire 1918 virus into mice. They began dying in as few as three days. Even more startling: In low doses, the H5N1 virus proved 10 times more virulent in mice than the 1918 strain.

Recreating the extinct virus was a spectacular achievement, but the resulting excitement was tinged with fear. After all, there is always a danger that an infectious agent can escape. Since 2003, four lab workers have become infected by SARS, and in 2004 a lab worker in Russia died of Ebola. Typical misgivings were expressed by the magazine New Scientist, which opined: "If someone catches the infection, it could prove impossible to contain. Is the work worth the risk ...?"

For many researchers, the answer is yes. "The risk that it will get out is very low," says virologist Erich Hoffman of St. Jude Children's Research Hospital in Memphis. "The benefit is that this work will provide us with information about the molecular basis of influenza transmission."

The U.S. government concurred. Only after thorough review by multiple biosafety committees was the virus's resurrection green-lighted.

Early results indicate that the key to the Spanish Flu's lethality is twofold. The proteins of its coat work together so that the virus can infect cells extremely deep in the lungs. And its polymerases--enzymes that drive replication--work with unusual speed. "We like to think of the polymerase as the engine of the virus," Tumpey says. "Those avian polymerases are just very efficient."

A SECOND TACTIC

The urgency of Tumpey's mission accelerates with every case of avian flu: 2006 began with 15 new victims in seven provinces of Turkey. At any time, the virus could learn the trick of human-to-human transmission. Or it could transform itself into a pandemic another way: by swapping genes between strains, a process called reassortment. For instance, if a chicken farmer who already has a human flu then catches H5N1 from his flock, cells infected with both viruses could produce virion with a mixture of their genes. Except for the Spanish Flu, every major influenza epidemic of the 20th century originated this way. In the case of H5N1, such a hybrid might turn out to be the "perfect flu," combining whirlwind transmissibility with extreme deadliness.

And since the world has never been exposed to this as-yet-nonexistent flu, it could sweep through the population unchecked by any immunity. To stave off that possibility, another team at the CDC, headed by influenza specialist Ruben Donis, is piecing together each of the 128 possible combinations of H5N1 and the most common human flu, H3N2.

It's possible that none of the reassorted strains will prove very harmful. But one could turn out to be a biological time bomb. Knowing which is which will help the CDC watch for the most dangerous strains, and even help develop defenses.

There's a dark irony in the fact that a disease-battling facility is building dangerous new pandemic strains. But that's the nature of the fight. Around the world, countless influenza virion are now penetrating host cells, multiplying, mutating, recombining and spreading out to infect anew. And in one lab in Atlanta, scientists are carefully shepherding along a parallel, artificial evolution. Both sides are groping toward a terrible secret. Which one finds it first could mean the difference between a global pandemic and none at all.